Osteoclasts are multinuclear cells of hematopoietic lineage, which function in the process of bone resorption. Typically, osteoclasts adhere to a bone surface and form a tight sealing zone. This activity is followed by extensive membrane ruffling on the surface of the osteoclasts. Such action creates an enclosed extracellular compartment on the bone surface that is acidified by proton pumps in the ruffled membrane and into which the osteoclast secretes proteolytic enzymes. The low pH of the compartment dissolves hydroxyapatite crystals at the bone surface, while the proteolytic enzymes digest the protein matrix. In this way a resorption pit is formed, after which the osteoclast releases from the surface of the bone. At the completion of this cycle, osteoblasts remodel the bone; that is, the osteoblasts deposit a new protein matrix, which is subsequently mineralized, at this zone.
Normally, a balance exists between the processes of bone resorption and new bone formation during remodeling. This normal balance of bone resorption and bone formation may be disrupted, resulting in a net loss of bone in each cycle of remodeling. Such net bone loss may lead to osteoporosis. Osteoporosis is characterized by reduced bone mass and disruptions in the microarchitecture of the bone. These characteristics may lead to fractures, which can result from a minimal amount of trauma. Typical sites of fractures include vertebral bodies, distal radius, and the proximal femur. However, because those suffering from osteoporosis have general skeletal weakness, fractures may occur at other sites.
Since osteoporosis is characterized by an increase in bone resorption with respect to bone formation, therapeutic agents that suppress bone resorption would be expected to provide a suitable treatment for osteoporosis. Administration of estrogens or calcitonin has been the bone resorption suppression treatment typically employed. However, these treatments do not always achieve the desired effect. Consequently, there is a continuing need for therapeutic agents that attenuate bone resorption in a subject in need of such attenuation.
Cathepsin K, which has also been called cathepsin O, cathepsin O2, and cathepsin X, is a member of the cysteine cathepsin family of enzymes, which are part of the papain superfamily of cysteine proteases. Other distinct cysteine protease cathepsins, designated cathepsin B, cathepsin C, cathepsin F, cathepsin H, cathepsin L, cathepsin O, cathepsin S. cathepsin V (also called L2), cathepsin W.  cathepsin Z (also called cathepsin X), have also been described in the literature. Cathepsin K polypeptide and the cDNA encoding such polypeptide have been disclosed in U.S. Pat. No. 5,501,969. A crystal structure for cathepsin K has also been disclosed in PCT Patent Application WO 97/16177, published May 9, 1997. It has been reported that cathepsin K is abundantly expressed in osteoclasts under normal conditions and may be the major cysteine protease present in these cells. (See Tezuka, et al., J. Biol. Chem., 1994, 269, 1106; Inaoka, et al, Biochem. Biophys. Res. Commun., 1995, 206, 89; and Shi, et al., FEBS Lett., 1995, 357,129.) This abundant selective expression of cathepsin K in osteoclasts suggests that this enzyme is essential for bone resorption. Thus, selective inhibition of cathepsin K may provide an effective treatment for diseases of excessive bone loss, such as osteoporosis.
The selective inhibition of cathepsin K may also be useful in treating other diseases. Such disorders include autoimmune diseases such as rheumatoid arthritis, osteoarthritis, neoplastic diseases, parasitic diseases, and atherosclerosis. For instance, cathepsin K is expressed in the synovium and synovial bone destruction sites of patients with rheumatoid arthritis (see Votta, B. J. et al.; J. Bone Miner. Res. 1997, 12, 1396; Hummel, K. M. et al., J. Rheumatol. 1998, 25, 1887; Nakagawa, T. Y. et al., Immunity 1999, 10, 207; Otsuka, T. et al., S. J. Antibiot. 1999, 52, 542; Li, Z. et al, Biochemistry 2000, 39, 529; Diaz, A. et al, Mol. Med. 2000, 6, 648; Moran, M. T. et al., Blood 2000, 96, 1969). Cathepsin K levels are elevated in chondroclasts of osteoarthritic synovium (See Dodds, R. A. et al., Arthritis Rheum. 1999, 42, 1588; Lang, A. et al., J. Rheumatol. 2000, 27, 1970). Neoplastic cells also have been shown to express cathepsin K (see Littlewood-Evans, A. J. et al, J. A. Cancer Res. 1997, 57, 5386; Komarova, E. A., et al., Oncogene 1998, 17, 1089; Santamaria, I., et al., Cancer Res. 1998, 58, 1624; Blagosklonny, M. V. et al., Oncogene 1999, 18, 6460; Kirschke, H. et al., Eur. J. Cancer 2000, 36, 787; Zhu, D.-M. et al., Clin. Cancer Res. 2000, 6, 2064). Cysteine protease inhibitors have been suggested as chemotherapy for parasitic diseases (see McKerrow, J. H. Int. J. Parasitol. 1999, 29, 833; Selzer, P. M. et al., Proc. Natl. Acad. Sci. U.S.A. 1999, 96, 11015; Caffrey, C. R. et al, Curr. Drug Targets 2000, 1, 155; Du, X. et al., Chem. Biol. 2000, 7, 733; Hanspal, M. Biochim. Biophys. Acta 2000, 1493, 242; Werbovetz, K. A. Curr. Med. Chem. 2000, 7, 835). Elastolytic cathepsins S and K are shown to be expressed in human atheroma (see Sukhova, G. K. et al., J. Clin. Invest. 1998, 102, 576-583; Parks, W. C. J. Clin. Invest. 1999, 104, 1167; Shi, G.-P. et al., J. Clin. Invest. 1999, 104, 1191; Cao, H. et al., J. Hum. Genet. 2000, 45, 94).
The present inventors have now discovered novel heterocycle substituted ketoamide derivative compounds that are inhibitors of serine and cysteine protease activities, more particularly, cathepsin family cysteine protease activities, and most particularly, cathepsin K activity. Such ketoamide derivatives are useful in the treatment of disorders associated with serine and cysteine protease activity, including osteoporosis, Paget's disease, hypercalcemia of malignancy, metabolic bone disease, osteoarthritis, rheumatoid arthritis, periodontitis, gingivitis, atherosclerosis, and neoplastic diseases associated with cathepsin K activity.